Nature and Mediators of Parietal Epithelial Cell Activation in Glomerulonephritides of Human and Rat

Abstract

Bowman's capsule parietal epithelial cell activation occurs in several human proliferative glomerulonephritides. The cellular composition of the resulting hyperplastic lesions is controversial, although a population of CD133(+)CD24(+) progenitor cells has been proposed to be a major constituent. Mediator(s) involved in proliferation and migration of progenitor cells into the Bowman's space have been poorly explored. In a series of 36 renal biopsies of patients with proliferative and nonproliferative glomerulopathies, dysregulated CD133(+)CD24(+) progenitor cells of the Bowman's capsule invade the glomerular tuft exclusively in proliferative disorders. Up-regulation of the CXCR4 chemokine receptor on progenitor cells was accompanied by high expression of its ligand, SDF-1, in podocytes. Parietal epithelial cell proliferation might be sustained by increased expression of the angiotensin II (Ang II) type-1 (AT1) receptor. Similar changes of CXCR4, SDF-1, and AT1 receptor expression were found in Munich Wistar Frömter rats with proliferative glomerulonephritis. Moreover, an angiotensin-converting enzyme inhibitor normalized CXCR4 and AT1 receptor expression on progenitors concomitant with regression of crescentic lesions in a patient with crescentic glomerulonephritis. These results suggest that glomerular hyperplastic lesions derive from the proliferation and migration of renal progenitors in response to injured podocytes. The Ang II/AT1 receptor pathway may participate, together with SDF-1/CXCR4 axis, to the dysregulated response of renal precursors. Thus, targeting the Ang II/AT1 receptor/CXCR4 pathways may be beneficial in severe forms of glomerular proliferative disorders.

Glomerular Regeneration: When Can the Kidney Regenerate from Injury and What Turns Failure into Success

“…Sustained antiproteinuric treatments with ACE inhibitors slow down disease progression and can even induce regression of glomerulosclerosis, associated with an increase in podocyte number, both in experimental and clinical settings [3,24]. While depleted podocytes can be replaced by RPCs, the actual regeneration observed during glomerular diseases is limited.…”

Cell Therapy for Kidney Injury: Different Options and Mechanisms - Kidney Progenitor Cells

“…Clonally expanded CD133+CD24+ cells also contribute to the regeneration of tubular structures and significantly ameliorate the functional kidney damage after their intravenous injection into severe combined immunodeficiency mice with AKI induced by rhabdomyolysis [19,20]. It has also been reported that these progenitor cells compose the hyperplastic glomerular lesion in several human proliferative glomerulonephritis [21]. …”

“…Renal stem/progenitor cells have been reported to exist or have been isolated from various locations in adult kidneys, including the renal papilla [16], tubular epithelial cells [17,18], Bowman's capsule [19,20,21], and the juxtaglomerular apparatus [22], via various identification methods such as label-retaining assays [16,17], clonogenic assays [18], flow cytometry using cell surface markers [19,20,21], lineage tracing [22], and side population (SP) assays [23,24]. Although these adult progenitors contribute to the epithelia of glomeruli and renal tubules like embryonic progenitors, they may represent cell populations different from embryonic nephron progenitors, with different gene expression profiles and cellular origins.…”

Drugs to Foster Kidney Regeneration in Experimental Animals and Humans

“…A key observation was that parietal epithelial cells lining Bowman's capsule expressing stem cell markers CD133 and CD24 are indicated as progenitor cells in the human kidney and give rise to podocytes and tubular cells (table 1) [23]. We recently observed [24] that glomerular hyperplastic lesions in human proliferative glomerulonephritis were derived from the dysregulated proliferation and migration of progenitor cells in Bowman's space in response to an inflammatory stimulus. The abnormal behavior of CD133+CD24+ cells could be the result of podocyte activation.…”

“…In proliferative disorders the expression of CXCR4, the receptor of the chemokine SDF-1, was higher in progenitor cells forming the hyperplastic lesions. On the other hand, podocytes activated by the inflammatory environment produced SDF-1, providing the ligand for CXCR4 receptors upregulated on progenitor cells, ultimately allowing their migration and proliferation [24]. The inflammatory environment is also sustained by Ang II which, through the AT 1 receptor, increases the production of reactive oxygen species, cytokines, and adhesion molecules.…”